Certain thiazole(3,2-a)benzimidazole compounds

ABSTRACT

COMPOUNDS OF FORMULA I AND FORMULA II HAVE BEEN PREPARED WHICH HAVE CNS DEPRESSANT AND ANTITUBERCULAR ACTIVITY:   1-(R2-OOC-(CH2)N-CH2-),2-((R3-PHENYL)-O-),R1-   1,3-THIAZETIDINO(3,2-A)BENZIMIDAZOLE (I)   1-(R2-OOC-(CH2)N-),2-(HO-),3-(R3-PHENYL),R1-2,3-DIHYDRO   THIAZOLO(3,2-A)BENZIMIDAZOLE   WHEREIN   R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HALOGEN, (LOWER) ALKYL, TRIFLUOROMETHYL, NITRO AND AMINO; R2 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND (LOWER) ALKYL; R3 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HALOGEN, (LOWER)ALKYL, TRIFLUOROMETHYL, NITRO, AMINO, PHENYL, HALOPHENYL AND (LOWER)PHENYL; N IS AN INTEGER OF FROM 1 TO 3;   AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF.

United States Patent 3,704,239 CERTAIN THIAZOLE[3,2-a]BENZIl\/IIDAZOLECOMPOUNDS Peter H. L. Wei, Springfield, and Stanley C. Bell, PennValley, Pa., assiguors to American Home Products Corporation, New York,N.Y. N0 Drawing. Filed Mar. 17, 1971, Ser. No. 125,378 Int. Cl. C07d99/08 US. Cl. 260306.7 8 Claims ABSTRACT OF THE DISCLOSURE Compounds ofFormula I and Formula II have been prepared which have CNS depressantand antitubercular activity:

\ S CH(CH 00 R:

PM i043 Twmncmm N lOH 1 wherein and the pharmaceutically acceptable acidaddition salts thereof.

DESCRIPTION OF THE INVENTION This invention is directed to thepreparation of new and novel pharmacologically active compounds. Thecompounds of the invention are those of Formulas I and II.

NH LO R Ra N s 011, ..002122 R:

-N I OH 11 wherein R is selected from the group consisting of hydrogen,halogen, (lower)alkyl, trifiuoromethyl, nitro and amino; R is selectedfrom the group consisting of hydrogen,

and (lower) alkyl;

"Ice

R is selected from the group consisting of hydrogen, halogen,(lower)alkyl, trifiuoromethyl, nitro, amino phenyl, halophenyl and(lower)alkylphenyl;

n is an integer of from 1 to 3;

and the pharmaceutically acceptable acid addition salts thereof.

The following reaction scheme illustrates the process of preparing thecompounds of the invention when R is lower alkyl:

/N\ s11 R, @cocmcmncmm NH i;

m w reflux m moH/ SCH(CHz) C02R4 NH {LOG -HX A to R| RI H10 or weak baseN s nmoolm R1 lhydrolysls N s 011.)..0 0,11 R1 N OH vrr

wherein R R and n are the same as hereinabove described; R, is(lower)alkyl and X is halogen.

In the above described procedure when the compounds are directlycyclized, glacial acetic acid, dimethoxy ethane or a correspondingalcohol may be employed as a solvent. It is preferred to heat thereactants at a temperature of from 80 to 100 for a period of from aboutthree to about fifteen hours. The crude product may then berecrystallized from a suitable solvent such as acetone or acetonitrile.When the compounds of Formulas IH and IV are admixed, it is preferred toemploy an alcohol wherein R of Formula IV is the same as R, of thealcohol as the solvent. The reactants are then refluxed for a period ofabout five to fifteen hours. The product may be separated byconventional techniques purified by recrystallization. Compounds ofFormula VI may be hydrolyzed to compounds of Formula VII by conventionaltechniques. The term weak base as employed herein is meant to includesodium bicarbonate, sodium carbonate, potassium carbonate, pyridine,triethylamine and the like.

Compounds wherein R is hydrogen may also be prepared as follows:

N\ SH R @coonwmncoon NH I In dimethoxy ethane VIII A80 to 100 (CH7)nCO2HR N on wherein R R and X are the same as hereinabove described.

In the above-described reaction scheme, it is preferred to heat thecompounds of Formulas III and VIII for a period of from about five toabout fifteen hours. The crude hydrohalide salts of Formula VII may thenbe purified by recrystallization from a suitable solvent. Thecyclization of Formula V to Formula VI may be accomplished by theaddition of water or a weak base.

The compounds of Formula I and Formula II where R, is lower alkyl, whilenot being limited thereto, are useful for the in vitro inhibition of M.tuberculosis. The compounds thus may be employed for example inhospitals, sanitariums and the like to effectively inhibit the causativeorganismsof tuberculosis by contacting infected areas and materials withaqueous dispersions of said compounds. Where R of the compounds ofFormula I and Formula II is hydrogen, the compounds are central nervoussystem depressants. Compounds of the invention have been tested bydetermining the minimal inhibitory concentration which will completelyinhibit M. tuberculosis, human type, strain H37Rv. The compounds ofFormulas I and II, wherein R is lower alkyl, have been found to beactive when admixed with the test organism in an aqueous dispersion at aconcentration of 50 ,ug./ml. Some compounds such as3-(p-chlorophenyl)-2,3-dihydro-3-hydroxythiazolo[3,2-a]benzimidazole-2-aceticacid, ethyl ester, have been found to be efiective at a concentration of0.5 ag/ml.

In the evaluation of the biological activity of the compounds ofFormulas I and II wherein R is hydrogen, the in vivo eflFects weretested as follows: The compound was administered orally orintraperitoneally to three mice (14 to 24 grams) at each of thefollowing doses: 400, 127, 40 and 12.7 milligrams per kilogram of hostbody weight (m.p.k.). The animals were watched for a minimum of twohours during which time signs of general stimulation (i.e.,increasedspontaneous motor activity, hyperactivity on tactilestimulation, twitching), general depression (i.e., decreased spontaneousmotor activity, decreased respiration), autonomic activity (i.e.,miosis, mydriosis, diarrhea) were noted.

The compounds of this invention induce central nervous system depressantefiects at a dose of 40 to 400 m.p.k. intraperitoneally. Thus thecompounds of Formulas I and II wherein R is hydrogen, have demonstratedutility as pharmacologically active compounds in experimental andcomparative pharmacology and are of value in the treatment of mammals,e.g., mice, rats, etc., who are responsive to treatment with centralnervous system depressant agents. Specifically the compounds may beadministered for the purpose of inducing a calming eifect in mammals.

The nomenclature employed to describe certain substituted compounds ofFormula I uses a parenthetical numbering system, e.g. 5(6) or 4(7), toidentify the positioning of substituents on the benzimidazolyl moiety.The reason for this type of nomenclature is because it is not possibleto fix the position of the substituent because of the proton shift dueto the NHC=N-group. This is in accordance with the nomenclature forimidazole type compounds set forth in Heterocyclic Compounds, R. C.Elderfield, editor, vol. 5, pp. 198, 199 and 238. To describe thecompounds of Formula II when the benzimidazolyl moiety is substituted,the alternative nomenclature is employed. This is because when thecompounds of Formula II are formed by ring closure the tautomerism ofthe NHC=N-moiety does not permit any absolute prediction as to thepositioning of the benzimidazolyl moiety.

EXAMPLE 1 3-(benzimidazol-2-ylthio)-3-(p-chlorobenzoyDpropionic acid,ethyl ester, hydrobromide An alcoholic solution of ethyl ester3-bromo-3- (p-chlorobenzoyl)propionic acid 16.0 g., 0.05 m.) and2-mercaptobenzimidazole (75 g., 0.05 m.) was heated on a steam bath for5 hours. After the solvent was removed the residue was dissolved inbenzene. The solid was collected and weighed 21.8 g. The crude materialwas recrystallized from ethanol. The pure ethyl ester of 3-(benzimidazol-Z-ylthio) 3 (p-chlorobenzoyl)-propionic acid hydrobromidehad a melting point of 168-170 C.

Analysis. 'Calcd. for C H ClN O S-HB1' (percent): C, 48.57; H, 3.86; N,5.98. Found (percent): C, 48.23; H, 4.09; N, 6.07.

IR spectrum showed a twin carbonyl ester 5.75; and keto 5.90u. The NMRspectrum showed aromatic protons at 7.8 6 (m.); methine at 5.9 6 (t.);acetyl methylene at 3.3 6; ethoxy at 4.1 (q.) and 1.2 6 (t.) and alsoexchangeable proton at 9.6 6.

EXAMPLE 2 3-(p-chlorophenyl)-2,3-dihydro-3-hydroxythiazolo[3,2-a]benzimidazole-2-acetic acid, ethyl ester The hydrobromide of theethyl ester '3-(benzimidazol- 2-ylthio) 3 (p-chlorobenzoyl)propionicacid (21.8 g.), was first ground and then added to 500 ml. of water. Thesuspension was stirred at room temperature for five hours. The solid wascollected and rinsed with water and sucked dry. Recrystallization of thecrude material from acetone, gave 15 g. of pure ethyl ester of3-(p-chlorophenyl)-2,3- dihydro 3 hydroxythiazolo[3,2-a]benzimidazoleacetic acid, M.P. -2 C.

Analysis.-Calcd. for C H ClN O S (percent): C, 58.68; H, 4.41; N, 7.21.Found (percent): C, 58.70; H, 4.44; N, 7.07.

IR spectrum showed the absence of amine salt absorption at 3.6 and ketosignal at 5.9/4. The NMR. spectrum: aromatic 7.56 (m.); methine 5.86(two sets of doublets); acetyl methylene 3.36; ethoxy 4.16 (q.) and 1.26(t.).

EXAMPLE 3 3-(p-chlorophenyl)-2,3-dihydro-3-hydroxythiazolo [3,2-a]benzimidazole-Z-acetic acid A dimethoxyethane solution ofZ-mercaptobenzimidazole (10.0 g., 0.066 m.) and3-bromo-3-(p-chlorobenzoy1)- propionic acid (17.4 g., 0.06 m.) washeated for 3 hours. The solid that separated from the chilled solutionwas collected, washed with dimethoxyethane, and dried to give 25 g. ofcrude hydrobromide salt of 3-(p-chloropheny1)- 2,3-dihydro 3hydroxythiazolo[3,2-a]benzimidazole- 2-acetic acid, M.P. 203205. The IRspectrum of the hydrobromide of the thiazolobenzimidazole acetic acidshowed only a single free carboxylic function at 6.0 1..

The above hydrobromide salt (17 g.) dissociated in water to give thefree acid, which was recrystallized from acetonitrile to give 12.0 g. ofpure 3-(p-chlorophenyl) 2,3-dihydro 3hydroxythiazolo[3,2-a]benzimidazole-2- acetic acid. M.P. 1603.

Analysis.Calcd. for C H ClN O S (percent): C, 56.59; H, 3.63; N, 7.76;S, 8.89. Found (percent): C, 56.33; H, 3.58; N, 7.47; S, 9.12.

The acid was also obtained by alkaline hydrolysis of the correspondingester followed by neutralization.

The hydrobromide of 3-(p-chlorophenyl)-2,3-dihydro-3-hydroxythiazolo[3,2-a] benzimidazole-Z-acetic acid was also preparedby heating a glacial acetic acid solution of 3-bromo-3-(p-chlorobenzoyl)propionic acid (11.64 g., 0.04 m.) and 2-mercaptobenzimidazole (6.00 g.,0.04 m.) on a steam bath for 3 /2 hours. The crude solid weighed 15 g.

EXAMPLE 4 3-(p-chlorobenzoyl)-3-(benzimidazole-Z-ylthio)propionic acid,methyl ester, hydrobromide 3-bromo-3-(p-chlorobenzoyl)propionic acid(60.0 g.) dissolved in methanol was heated to reflux for two days. Thesolvent was removed, and the residue dissolved in benzene. The benzenesolution was washed with sodium bicarbonate and then dried overanhydrous magnesium sulfate. After the benzene was removed, a heavy oil(64 g.) was obtained. The IR spectrum: ester 5.75,u.; C=O 5.9,u. N.M.R.:aromatic 8.06 (m.); methine 5.66 (two sets of doublets); OCH 3.76 (s.);methylene 3.36 (two sets of quartets).

The methyl ester was also prepared by methylation of the correspondingacid with diazomethane.

A methanol solution of 3-bromo-3-(p-chlorobenzoyl) propionic acid,methyl ester (6.1 g., 0.02 m.) and 2-mercaptobenzimidazole (3.0 g., 0.02m.) Was heated to reflux for six hours. After filtration the solutionwas concentrated. The oily residue was treated with benzene and thesolid was collected. The crude material was recrystallized from amixture of methanol and acetone to give 4.5 g. of pure material, M.P.182-5.

Analysis.-Calcd. for C I-I ClN O S-HBr (percent): C, 47.42; H, 3.54; Br,17.53; Cl, 7.78; N, 6.15; S, 7.03. Found (percent): C, 47.32; H, 3.64;Br, 17.72; Cl, 7.86; N, 6.25; S, 7.03.

IR (KBr): amine Hbr 3.6 1.; ester 5.8 1; C=O 6.0 N.M.R.; aromatic 7.66;methine 6.46; methylene and OCH 3.76.

EXAMPLE 5 3-(benzimidazol-Z-ylthio)-3-benzoylpropionic acid, ethylester, hydrobromide The 3-benzoylpropionic acid was esterified inabsolute ethanol in the presence of HCl. The ester was brominated inchloroform to give 3-bromo-3-beuzoylpropionic acid, ethyl ester which isan oil. IR: C-H 3.4 1; ester 5.75;t; C=O 5.9a. N.M.R.: aromatic 7.66(m.); methine 5.56 (two sets of doublets); methylene 3.256 (two sets ofquartets); ethoxy 4.16 (q.) and 1.26 (L).

An ethanol solution of 3-bromo-3-benzoylpropionic acid, ethyl ester(14.25 g., 0.05 m.) and Z-mercaptobenzimidazole (7.5 g., 0.05 m.) washeated to reflux for six hours. After filtration the solution wasconcentrated. The residue upon treatment with 50 ml. acetone gave somesolid which was collected. The crude material was recrystallized fromactone. The pure material weighed 14.5 g. and had a melting point ofl267.

Analysis.-Calcd. for C H N O S-HBr (percent): C, 52.42; H, 4.40; Br,18.35; N, 6.44; S, 7.37. Found (per-- cent): C, 52.46; H, 4.28; Br,18.08; N, 6.39; S, 7.43.

IR: 3.6 1 amine HBr; ester 5.7a; C=O 5.9g. N.M.R.: aromatic 7.56 (m.);methine 5.96; methylene 3.26; ethoxy 4.06 (q.) and 1.16 (t.).

6 EXAMPLE 62,3-dihydro-3-hydroxy-2-phenylthiazolo[3,2-a]benzimidazole-2-aceticacid, ethyl ester A benzene-Water mixture of 3-(benzimidazol-2ylthio)-3-benzoylpropionic acid, ethyl ester, hydrobromide (9.0 g.), was stirredand neutralized with a dilute NaI-ICO solution. The layers wereseparated. The organic layer was dried over anhydrous magnesium sulfate.After benzene was removed, the residue was treated with acetone and thesolid (7.0 g.) was collected. The crude material was recrystallized fromacetone to give pure compound, M.P. 129-31".

Analysis.-Calcd. for C H N O S (percent): C, 64.39; H, 5.12; N, 7.91; S,9.05. Found (percent): C, 64.31; H, 5.18; N, 7.63; S, 9.08.

IR: OH 3.2 ester 5.75p.: N.M.R.: aromatic 7.46 (m.); methine 5.66;methylene 3.26; ethoxy 4.16 (q.) and 1.26 (t.).

EXAMPLE 72,3-dihydro-3-hydroxy-3-phenylthiazolo[3,2-a]benzimidazole-2-aceticacid, methyl ester, hydrobromide 3-benzoylpropionic acid g.) wasesterified with methyl alcohol which was saturated with HCl. After thesolution was heated to reflux overnight, the solvent was removed. Theresidue was dissolved in benzene, and the benzene solution was washedwith a dilute NaHCO solution and dried over anhydrous MgSO After removalof benzene there was obtained 95 g. of 3-benzoylpropionic acid, methylester. IR: ester, 5.75 keto 9.0g.

The above keto ester was brominated in a chloroform solution with 79 g.of bromine. The 3-bromo-3-benzoylpropionic acid, methyl ester (134 g.)was an oil. IR: ester, 5.75 1; keto 9.0,u.. N.M.R. (CdCl aromatic, 7.76(m.); methine, 5.56 (two sets of doublets); acetylmethyl, 3.66 (two setsof quartets); CH 0, 3.76 '(s.).

(A) A glacial acetic acid solution of Z-mercaptobenzimidazole (2.5 g.,0.0166 111.) and 3 bromo 3 benzoylpropionic acid, methyl ester (4.5 g.,0.02 m.) was heated on a steam bath for one hour. After the solvent wasremoved, the residue was first washed with anhydrous ether and thendissolved in a small amount of acetone. The crude solid material (3.1g.) which separated out from acetone was collected and recrystallizedfrom the same solvent to give pure compound, M.P. -7

Analysis.-Calcd. for C I-I N O S-HBr (percent): C, 51.31; H, 4.07; Br,18.97; N, 6.65; S, 7.61. Found (percent): C, 51.60; H, 4.28; Br, 19.05;N, 6.69; S, 7.84.

IR: OH, 3.25 amine HBr, 4.0 1.; ester, 5.-85,u.. NMR (DMSO): aromatic,7.56 (m.); methine, 5.96 (t.) methylene, 3.36 (two singlets); OCH 3.66(s.); exchangeable, 12.16.

l(B) 2,3 dihydro 3 hydroxy 3 phenylthiazolo- [3,2-a1benzimidazole 2acetic acid, methyl ester, hydrobromide was also prepared by heating toreflux a methanol solution of 3-bromo-3-benzoylpropionic acid, methylester (10.8 g., 0.04 m.) and 2 mercaptobenzimidazole (6.0 g., 0.04 m.)for five hours. The crude material, (13.5 g.) after removal of solvent,was recrystallized from acetonitrile.

EXAMPLE 8 3- [5 (6 -aminobenzimidazol-2-ylthio] -3-(p-chlorobenzoyl)propionic acid, ethyl ester, hydrobromide \An ethanolsolution of 3 bromo 3 (p-chlorobenzoyl)propionic acid, ethyl ester (12.8g., 0.04 m.) and 5 amino 2 benzimidazolethiol (6.6 g., 0.04 m.) washeated to reflux for 3 /2 hours. After the solution was treated withDarco, the solvent was removed. The oily residue was treated withbenzene to give 16 g. of crude material. The crude material wasrecrystallized from a mixture of C H OH and acetone, dec. at 250.

Analysis.Calcd. for C H ClN O S-HBr (percent): C, 47.18; H, 3.75; Br,16.52; Cl, 7.33; N, 8.69; S, 6.63. Found (percent): C, 46.83; H, 3.90;Br, 16.00; Cl, 7.10; N, 8.63; S, 7.02.

IR: amine HBr, 3.5 1; ester, 5.7,u; ketone, 5.85 NMR (DMSO): aromatic7.686 (m.); methine, 5.96; methylene, 3.36; ethoxy, 4.16 (q.) and 1.16(t.), also exchangeable EXAMPLE 9 3 (p-chlorophenyl) 2,3 dihydro 3hydroxythiazolo[3,2-a]benzimidazole 2 acetic acid, methyl ester Asuspension of 3 (p-chlorobenzoyl) 3 (benzimidazol 2 ylthio)propionicacid, methyl ester, hydrobromide (12.0 g.) in a mixture of chloroformand water was stirred and neutralized with a dilute solution of NaHCOg.The layers were separated. The chloroform layer was washed once withwater and dried over anhydrous MgSO After removal of the solvent, theoily residue was dissolved in acetone. From the acetone solution 8.2 g.of the product (M.P. 132-4) was obtained.

Analysis.-Calcd. for C H ClN O S (percent): C, 57.68; H, 4.03; Cl, 9.46;N, 7.48; S, 8.56. Found (percent): C, 57.20; H, 3.98; Cl, 9.27; N, 7.32;S, 8.73.

'IR: OH, 3.3 1.; ester, 5.75 2. NMR (DMSO); aromatic, 7.56 (m.);methine, 5.86; OCH 3.66 (s.); methylene,

EXAMPLE 10 3- (p-chlorobenzoyl -3- [5 (6) -nitrobenzimidazol-2-ylthio]-propionic acid, ethyl ester, hydrobromide A glacial acetic acidsolution of 3 bromo 3 (pchlorobenzoyl)propionic acid, ethyl ester (12.7g., 0.04 m.) and 5 nitro 2 benzimidazolethiol (7.8 g., 0.04 m.) washeated on a steam bath for 15 hours. The yellow solid was collected. Themother liquor upon concentration gave more solid. The crude material wasrecrystallized from ethanol. The pure product weighed 13 g. and meltedat 21820.

Analysis.Calcd. for C H ClN S-HBr (percent): C, 44.32; H, 3.33; Br,15.52; Cl, 6.89; N, 8.16; S, 6.23. Found (percent): C, 44.38; H, 3.32;Br, 15.18; Cl, 6.74; N, 7.81; S, 5.98.

The IR spectrum showed absorptions for ester at 5.8;.0, keto group at6.0 1, N0 group at 6.7 and 7.5g. The NMR spectrum (DMSO-d showedaromatic protons at 8.16 (m.), a methine proton at 6.16 (t), twomethylene protons at 4.26 (q.), two methylene protons at 3.36, threemethyl protons at 1.26 a triplet exchangeable proton at 9.86.

EXAMPLE 11 3 (p-chlorophenyl) 2,3 dihydro 3 hydroxy-7 (or 6)-nitrothiazolo[3,2-a] benzirnidazole 2 acetic acid, ethyl ester,hydrobromide A mixture of 3 (p-chlorobenzoyl) 3 [5 (or 6)-nitrobenzimidazol-Z-ylthio]-propionic acid, ethyl ester hydrobromide(9.0 g.) in chloroform and a dilute sodium bicarbonate solution wasstirred at room temperature for two hours. A small amount of solid wasfiltered oil. The layers were separated. The chloroform layer was washedwith water and dried over anhydrous magnesium sulfate. After chloroformwas removed, the residue was treated with benzene and the solid wascollected. The crude material weighing 7.2. g. was recrystallized frombenzene and the pure compound melted at 99-1019.

Analysis.Calcd. for C H ClN O S (percent): C, 52.59; H, 3.72; Cl, 8.17;N, 9.69; S, 7.39. Found (percent): C, 52.51; H, 3.66; Cl, 8.64; N, 9.74;S, 7.36.

The IR spectrum showed absorption for ester 5.75p., nitro group at 6.55and 7.511..

R: wherein R R R and n are defined below:

R; R3 R3 1| 5(6) amino Ethyl 4-methyl 2 4(7) methyl n-Propyl 4-bromo 15(6) chloro Hydrogen. 4-trifluoromethyl 3 5(6) bromn Methyl 3- 2 4(7)iodo Hydro en Hydrmmn 2 5(6) fluoro Ethyl -bromo 3 5(6) ethyl Hydro en3- 2 5(6) n-propyl Methyl 4-nitro 1 4(7) methyl do Pheny 1 4(7) choroEthyl p-Tolyl 2 5(6) hydrogen Methyl. p-Chloropheuyl 1 5(6)trifluoromethyl- Ethyl..- e-fluoro 3 Hydroge -ethyl 3 m-Bromophenyl- 2By methods analogous to those employed above the following compounds areprepared:

wherein R R R and n are defined below:

6 or 7 amino Ethyl 4-methyl 2 5 or 8 methyl n-Propyl 4-br0rno 1 6 or 7chloro Hydrogen 4-trifluoromethyl 3 6 or 7 bromo Methyl B-amino. 2 5 or8 lodo Hydr Hydro en 2 6 or 7 fiuoro- Ethyl 4-bromo 3 6 or 7 chloro-Methyl Phenyl- 1 Do. Ethyl.-. p-Tolyl. 2

6 or 7 ethyl.-- Hydroge 3-amino. 2 6 or 7 n-propyl MethyL. 4-nltro. 1 6or 7 trlfluoromethyl..- Ethyl 4-fluoro-. 3 6 or 7 hydrogen Hydrogem-4'ethyl 3 D MethyL. 3-n-propyl- 2 p-Chlorophenyl 1 m-Bromophenyl- 2 N' s011.)..00116 R1 wherein R is selected from the group consisting ofhydrogen, halogen, (lower)alkyl, trifluoromethyl, nitro and amino; R isselected from the group consisting of hydrogen and lower alkyl; R, isselected from the group consisting of hydrogen, halogen, (lower)alkyl,trifluoromethyl, nitro, amino, phenyl, halophenyl and (lower)alkylphenyl; n is an integer of from 1 to 3; and the pharmaceuticallyacceptable acid addition salts thereof.

2. A compound as defined in claim 1 which is3-(pchlorophenyl)-2,3-dihydro 3 hydroxythiazolo[3,2-a]benzimidazole-Z-acetic acid, ethyl ester.

3. A compound as defined in claim 1 which is3-(pchlorophenyl)-2,3-dihydro 3 hydroxythiazolo[3,2-a]benzimidazole-Z-acetic acid.

4. A compound as defined in claim 1 which is3-(pchlorophenyl)-2,3-dihydro 3 hydroxythiaz0lo[3,2-a]benzimidazole-Z-acetic acid, hydrobromide.

5. A compound as defined in claim 1 which is 2,3- dihydro 3hydroxy-3-phenylthiazolo[3,2a]benzimidazole-2-acetic acid, ethyl ester.

6. A compound as defined in claim 1 which is 2,3-di- 10 hydro-3-hydroxy3 phenylthiazolo[3,2-a]benzimidazole-2-acetic acid, methyl ester,hydrobromide.

7. A compound as defined in claim 1 which is3-(pchlorophenyl)-2,3-dihydro 3 hydroxythiazolo[3,2a]benzimidazole-Z-acetic acid, methyl ester.

8. A compound as defined in claim 1 which is3-(pchlorophenyl)-2,3-dihydro 3hydroxy-7(6)-nitrothiazolo[3,2-a]benzimidazole-Z-acetic acid, ethylester, hydrobromide.

No references cited.

NICHOLAS S. RIZZO, Primary Examiner R. J. GALLAGHER, Assistant ExaminerUS. Cl. X.R.

